FR2483233A1 - CARDIOTONIC COMPOSITIONS CONTAINING AMINOPHENYLPYRIDINES, NOVEL AMINOPHENYLPYRIDINES AND THEIR PREPARATION - Google Patents

Abstract

THE INVENTION RELATES TO A CARDIOTONIC COMPOSITION CONTAINING AS ACTIVE COMPONENT A COMPOUND OF FORMULA: (CF DRAWING IN BOPI) OR ONE OF ITS PHARMACEUTICALLY ACCEPTABLE SALTS OR R IS H, CH, CH OR OH, R IS H, CH OR CH, R AND R ARE EACH H OR CH, AND AC IS H OR A HYDROXYACETYL, ACETOXYACETYL, A-HYDROXYPROPIONYL, A-ACETOXYPROPIONYL, METHOXYACETYL, 2-BUTENOYL OR CARBAMYL GROUP, OR WHEN A-HYDROXYPROPIONYL, A-ACETOXYPROPIONYL, METHOXYACETYL, 2-BUTENOYL OR CARBAMYL GROUP, OR WHEN A-FORMAL 4, ACETOXYACETYL, AND ACETOXYACETYL GROUP, IS POSITION 4, AND PEAC N-PROPANOYL, 2,2-DIMETHYL-N-PROPANOYL OR 3-CARBOXYPROPANOYL, AND WHEN NHAC IS IN POSITION 3, AC MAY ALSO BE AN ACETYL GROUP. THE COMPOUNDS OR AC IS NEITHER A HYDROGEN ATOM OR AN ACETYL GROUP ARE NEW. THESE COMPOUNDS ARE PREPARED BY ACYLATION OF THE CORRESPONDING PYRIDINES AND OBTAINING, IF DESIRED, AN ACID ADDITIONAL SALT.

Description

This invention relates to cardiotonic compositions for use in

  increase cardiac contractility and including aminophenylpyridines and such new

  compounds and their preparation.

  Heilbron et al. [J. Chem. Soc. 1940, 1279], describe

  as intermediates in the preparation of 3- and 4-pyridyl-

  diphenyls the following compounds: -3-aminophenyl-

  pyridine, (4-aminophenylpyridine and -f-4-amino)

  phenylpyridine and the N-acetylated derivatives of each of the

  compounds, including the hydrochloride of the

  acétamidophénylpyridine; these three aminophenylpyridines are commonly called 3- (3-pyridinyl) benzene-amine, 4- (3-pyridinyl) benzene-amine and 4 (4-pyridinyl) benzene-amine, respectively. U.S. Patents Nos. 3,753,993 and 3,907,808 disclose, as intermediates for the preparation of quinoline-type antibacterial agents, diverseg3- (pyridinyl).

  substituted) benzene-amines o the pyridinylpest group sub-

  located, inter alia, by lower alkyl radicals, OH

  etc., represented by 3- (2-methyl-4-pyridinyl) -

  benzene-amine, 3- (2-hydroxy-6-methyl-4-pyridinyl) benzene

  amine, 3- (2,6-dimethyl-4-pyridinyl) benzene-amine,

  3- (2,6-diethyl-4-pyridinyl) benzenamine, 3- (2,5-dimethyl)

  4-pyridinyl) benzene-amine, 3- (3-methyl-4-pyridinyl) benzene

  amine, 3- (2-ethyl-4-pyridinyl) benzene-amine and 3- (2,3-

  dimethyl-4-pyridinyl) benzene-amine. The U.S. Patent No. 4,118,557 describes the derivatives

  N- (lower alkanoyl) various 3- (pyridinyl) benzene-

  amines, represented as follows: N-acetyl derivatives,

  N-formyl, N-propanoyl, N-butanoyl and N-hexanoyl

  3- (4-pyridinyl) benzene amine; and the N-acetyl derivatives of 3- (2-methyl-4-pyridinyl) benzene-amine,

  3- (3-pyridinyl) benzene-amine, 3- (2,6-dimethyl)

  4-pyridinyl) benzene-amine and 3- (2-ethyl-4-pyridinyl)

benzenamine.

  One aspect of the invention relates to a cardio

  tonic for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable inert carrier and, as an active component, a

  effective amount of a 4-4 (or 3) -AclN-phenyl-2-R2-3-R3-

  R-R5-6-R6-pyridine cardiotonic of formula I 2 R3 N NHAc I NHAC

R6 R5

  in which R2 is a hydrogen atom or a methyl, ethyl or hydroxy group, R6 is a hydrogen atom or a methyl or ethyl group, R3 and R5 are each a hydrogen atom or a methyl group and Ac denotes a hydrogen, hydroxyacetyl, acetoxyacetyl, β-hydroxypropionyl, o-acetoxypropionyl, methoxyacetyl, 2-butenoyl or carbamyl radical and, when NHAc is attached to the 4-position of the phenyl ring, Ac may also denote a radical

  formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-

  carboxypropanoyl, and when NHAc is attached to the 3-position of the phenyl ring, Ac may also designate a group

  acetyl, or a pharmaceutically acid addition salt thereof

  acceptable. The preferred compounds are those where the active component is defined as above having an R2 group which is a hydrogen atom or a methyl, ethyl or hydroxy group, R3, R5 and R6 each being a hydrogen atom or a hydrogen atom. methyl group and Ac is a hydrogen atom, a formyl group only when

  NHAc is attached to the 4-position of the phenyl nucleus, hydroxyl

  acetyl, o-hydroxypropionyl or carbamyl, or their

  pharmaceutically acceptable salts.

  Cardiac contractility can be increased in a patient in need of such treatment by administering to this patient, either orally or parenterally, in solid or liquid dosage form, an effective amount of the

  4-4 (or3) -NH-phenyl -2-R2-3-R3-5-R5-6-R6-pyridine cardio-

  tonic of formula I as defined above.

  The invention also relates to a new 4- [4 (or 3) -

  Ac'-NH-phenyl) -2-R2-3-R3-5-R5-6-R6-pyridine of formula II

R2 R3

1 II

Neither NHACa

R6 R5

  R2 is a hydrogen atom or a methyl group,

  ethyl or hydroxy, R6 is a hydrogen atom or a group

  methyl or ethyl D R3 and R5 are each a hydrogen atom or a methyl group, and Ac 'is a hydroxyacetyl, acetoxyacetyl, 0-hydroxypropionyl, O-acetoxypropionyl, methoxyacetyl, 2-butenoyl or carbamyl group;

  and when NHAc 'is attached to the 4-position of the phenyl ring

  Ac 'is also a formyl, n-propanoyl, 2,2-dimethyl-npropanoyl or 3-carboxypropanoyl group; or an acid addition salt thereof. Preferred compounds of this aspect of this invention are those wherein R2 is hydrogen, methyl, ethyl or hydroxy; R3, R5 and R6 are each a hydrogen atom or a group

  methyl and Ac 'is a hydroxyacetyl group, oc-hydroxy-

  propionyl, carbamyl or, when NHAc 'is fixed in position

  4 of the phenyl ring, Ac 'is a formyl group or n-

  propanoyl, or an acid addition salt thereof.

  In fact,. the new compounds of formula II have the same substituents as the compounds of formula I, but Ac 'does not include the hydrogen atom or the group

Acetyl defined for Ac.

  A 4- [4 (or 3) -aminophenyl] -2-R2- may be reacted

  3-R3-5-R5-6-R6-pyridine with an acylating agent providing

  Ac 'to obtain 4- (or 3) -Ac'-aminophenyl -2-R2-3-R3-

  -R5-6-R6-pyridine, where Ac ', R2, R3, R5 and R6 are such that

  defined below for formula II.

  The compounds of formulas I and II can be used both in the free base form and in the form of the acid addition salts and both forms are within the scope of the invention. Acid addition salts are simply a more convenient form for use; and in practice, the use of the salt form is inherently consistent with the use of the base form. The acids which can be used to prepare the acid addition salts include (preferably in the case of formula II and necessarily with the composition using the compound of formula I) those which produce, when combined with the free base, pharmaceutically acceptable salts that is to say salts whose anions are relatively harmless vis-à-vis the animal body at pharmaceutical doses of salts so that the beneficial cardiotonic properties inherent to the free base do not are not vitiated by side effects attributable to anions. In the setting

  of the invention, it is convenient to use chlorine

  hydrate or lactate. However, other pharmaceutical salts

  Suitable compounds within the scope of the invention are those obtained from mineral acids such as hydrobromic acid, sulfuric acid, phosphoric acid and sulfamic acid; and organic acids such as acetic acid, citric acid, tartaric acid, methanesulfonic acid, ethanesulfonic acid, benzenesulfonic acid, p-toluenesulfonic acid, acid cyclohexylsulfamic acid, quinic acid, etc ..., respectively giving the hydrobromide, sulfate, phosphate sulfamate, acetate, citrate, tartrate, methanesulfonate ethanesulfonate, benzenesulfonate, p-toluenesulfonate

cyclohexylsulfamate and quinate.

  The acid addition salts of the compounds of formulas I and II are prepared by dissolving the free base in an aqueous or aqueous-alcoholic solution or other suitable solvents containing the appropriate acid, and isolating the salt by evaporation. of the solution, or by reacting the free base and the acid in an organic solvent, in which case the salt separates directly or can be obtained

by concentration of the solution.

  Although the pharmaceutically acceptable salts of the novel compounds of formula II are preferred, all acid addition salts are within the scope of the invention. The acid addition salts are all usable as a source of the free base even if the particular salt itself is only sought as an intermediate product, for example when the salt is formed only for purposes of purification or identification, or when it is used as an intermediate for the preparation of a pharmaceutically acceptable salt by ion exchange procedures. The molecular structures of the novel compounds of formula II have been assigned on the basis of data provided by the infrared, nuclear magnetic resonance and mass spectra, and by the correspondence between the values.

  calculated and found for elemental analysis.

  The reaction of 4- [4 (or 3) -aminophenyl] -

  2-R2-3-R3-5-R5-6-R6-pyridine with an acylating agent

  providing Ac 'to obtain 4-f 4 (or 3) -Ac'-aminophenyl -

  2-R2-3-R3-5-R5-6-R6-pyridine of formula II, using various acylating agents, for example by heating directly with formic acid or by heating with an acid in benzene, toluene or xylene in a bottle equipped with a water separator, by heating the acid with an anhydride in a suitable solvent or by reacting an acid chloride in an inert solvent, namely chloroform, dichloride methylene, pyridine, etc., in the presence of an acid acceptor, for example the

  pyridine, K 2 CO 3, etc ..., preferably at about 0 to 5 C.

  These acylations are better illustrated below.

  The following examples will illustrate the invention without

however, limit it.

Example 1

  N- [4- (4-Pyridinyl) phenyl] formamide A mixture containing 11.1 g of 4- (4-pyridinyl) benzene-amine and 150 ml of 97% formic acid is stirred under reflux for 2.5 hours. then the mixture is concentrated under vacuum. The residue is suspended in water,

  alkalize the mixture with a solution of ammonium hydroxide

  The solid is collected, washed with water and recrystallized from ethanol to give 4.4 g of product, m.p. C. A second crop of product weighing 3.9 g is obtained by concentrating the filtrate; and a third crop weighing 1.4 g is isolated by concentration of the second

  filtrate. We combine the first two harvests and we recrystallize

  the mixture in isopropyl alcohol and dried at 80 ° C in a vacuum oven for 18 hours, which

  gives 7 g of N- [4- (4-pyridinyl) phenyl] formamide, m.p. 188-

   C. In another run utilizing the foregoing procedure starting from 13.6 g of 4- (4-pyridinyl) benzenamine and 175 ml of 97% formic acid and using a reflux period of more than 4 hours and a half. and after concentration of the reaction mixture under vacuum, the residue is taken up in 300 ml of water, the mixture is treated

  aqueous solution with bleaching charcoal and filtered, and

  Linse the aqueous acidic filtrate with an ammonium hydroxide solution and cool. The separated solid is boiled in isopropyl alcohol to drive off the water; the solution is concentrated to 200 ml; and we add to the solution

  partially cooled, a slight excess of hydrochloric acid

  gene in ethanol. The suspension is diluted with

  ether to ensure complete precipitation of the product.

  The precipitate is collected and dried at 80 ° C. in a vacuum oven for 16 hours to give 17.2 g of N- [4- (4-pyridinyl) phenyl] formamide hydrochloride.

  m.p. 249-250.5 C with decomposition.

Example 2

  2-Methoxy-N- [4- (4-pyridinyl) phenyl] acetamide The mixture is refluxed with stirring for 12 hours in a flask equipped with a condenser and a water separator, a mixture containing 12.8 g of 4 - (4-pyridinyl) benzeneamine, 17.2 ml of methoxyacetic acid and 250 ml of xylene. The reaction mixture is then concentrated in vacuo and the residue is suspended in water and the mixture is basified with potassium carbonate solution. The yellow-brown solid is collected, dissolved in hot isopropyl alcohol, the hot solution is filtered to remove a small amount

  of insoluble materials and the filtrate is allowed to cool.

  The solid which separates is collected and dried under vacuum

  at 90 ° C. for 18 hours, and 13.7 g of 2-methoxypropionate are obtained.

  N- [4- (4-pyridinyl) phenyl] acetamide, m.p. 177-178.5 C.

Example 3

  N- [4- (4-pyridinyl) phenyl] urea 39.2 g are dissolved in 150 ml of hot acetic acid

  4- (4-pyridinyl) benzene amine and 230 ml of water are added.

  The solution is stirred and heated to 55 ° C. on a steam bath and then a hot solution containing 74.1 g of potassium cyanate in 460 ml of water is added dropwise over one hour using a dropping funnel. having a long rod that dips well below the surface of the reaction mixture. The reaction temperature is maintained at 55-60 ° C throughout the addition. A yellow solid begins to form once about one-third of the potassium cyanate has been added. The reaction mixture is allowed to cool, continuing to stir for about

  30 minutes then let it sit for two hours.

  To the stirred solution, about 60 ml of concentrated ammonium hydroxide is added to a pH of 8. The mixture is carefully cooled in an ice bath and the separating solid is collected, dried thoroughly with water and dried. fresh water and squeeze it with suction to keep it as dry as possible. The wet solid is recrystallized from 400 ml of dimethylformamide using bleaching charcoal and the crystallized material is collected, washed with ethanol and dried in a vacuum oven at 60 ° C. to obtain

  19.3 g of N- [4- (4-pyridinyl) phenyl] urea, m.p. 245-247 C.

Example 4

  2-Hydroxy-N- [4- (4-pyridinyl) phenyl] propanamide The mixture is refluxed with stirring for more than one hour and three quarters in a flask equipped with a condenser and a

  water separator, a mixture containing 10.2 g of 4- (4-

  pyridinyl) benzene-amine, 18.8 g of 80% lactic acid and 300 ml of xylene. The resulting slurry is concentrated in vacuo, the residue is treated with water and the aqueous mixture is basified with 10% potassium carbonate solution. The solid is collected, washed with water and recrystallized from isopropyl alcohol (final volume 100 ml). Drying the resulting product at 90 ° C. in a vacuum oven for 16 hours gives 6.24 g of 2-hydroxy-N-1 [4- (4-pyridinyl) phenyl] propanamide.

m.p. 236-238 C.

  Following the procedure described below in Example 10 but using 3-methylbutanoic acid chloride phace in an equimolar amount of 2-acetoxypropanoyl chloride, it can be seen that

  obtain 2-acetoxy-N- [4- (4-pyridinyl) phenyl] propanamide.

Example 5

  2-Hydroxy-N-- [4- (4-pyridinyl) phenyl] acetamide The mixture is refluxed for more than 4 hours, with stirring in a flask equipped with a condenser and a

  water separator, a mixture containing 15 g of 4- (4-

  pyridinyl) benzene-amine, 28.25 g of 70% glycolic acid and 250 ml of xylene. The reaction mixture is concentrated in vacuo; the residue is stirred with 250 ml of water and then the aqueous mixture is basified with potassium carbonate solution. The solid is collected, recrystallized from isopropyl alcohol (final volume 250 ml) and dried at 90 ° C. in a vacuum oven for 18 hours, to give 13.8 g of 2-hydroxy-N- [ 4- (4-pyridinyl) phenyl acetamide, mp 231-234 C. A second harvest of 1.39 g of product is obtained. The combined crops are recrystallized from acetonitrile (final volume 1500 ml) and the product is dried at 180 ° C. under vacuum for more than 16 hours. We

  dissolves the recrystallized product in 300 ml of dimethyl

  formamide and the solution is treated with a slight excess of hydrochloric acid in ethanol. The suspension is diluted with ether, the precipitated product is collected and dried in a vacuum oven for 16 hours at 125 ° C.

  and 16.88 g of 2-hydroxy-N-hydrochloride are obtained.

  [4- (4-pyridinyl) phenyl] acetamide, m.p. 270-274 C.

  By following the procedure described below in Example 10 but using instead of 3-methylbutanoic acid chloride an equimolar amount of acetoxyacetyl chloride, it can be seen that it is possible to obtain

  2-acetoxy-N- [4- (4-pyridinyl) phenyl] acetamide.

Example 6

  N- [4- (4-Pyridinyl) phenylpropanamide 8.51 g of 4- (4-pyridinyl) benzene-amine

  to a solution containing 38.8 ml of propargic acid anhydride

  in 100 ml of chloroform and the dissolution is

  incomplete after 24 hours at room temperature.

  The reaction mixture is then stirred under reflux for 8 hours, and the hot suspension is filtered through diatomaceous earth and the filtrate is concentrated in vacuo. The residue is suspended in water, the mixture is basified with ammonium hydroxide solution, the solid is collected and washed with water. The solid is taken up in mrl of hot isopropyl alcohol and to the solution is added 250 ml of hot water. The resulting solution is filtered and then allowed to cool, causing separation of an oil which crystallizes on standing. The crystalline material is collected and dried under vacuum at 80 ° C. for hours, and 10.66 g of N- [4- (4-pyridinyl) are obtained.

  phenylpropanamide, m.p. 179-181 C.

Example 7

  2,2-Dimethyl-N- [4- (4-pyridinyl) phenyl] propanamide

  To a mixture containing 8.51 g of 4- (4-pyridinyl) benzene

  amine suspended in 100 ml of ethylene chloride is added with stirring a solution containing 13.27 g of potassium carbonate in 60 ml of water. To the resulting solution, cooled to about 5 ° C., is added in stirring for 20 minutes.

  a solution containing 4.7 g of 2,2-dimethylchloride

  propanoyl in 40 ml of ethylene chloride, and stirring is continued in the cold for about 4 hours and then without external cooling for about 16 hours. Filter

  the solution and separating the layers contained in the filtrate.

  The ethylene chloride layer is concentrated in vacuo to give a yellow orange solid. Since the acylation of the insoluble pyridinyl-benzene-amine is incomplete, the previous filter cake of the reaction mixture is taken up in isopropyl alcohol and concentrated

  the vacuum solution to expel alcohol and water.

  The residue is combined with the orange-yellow solid obtained previously from the ethylene dichloride layer and with 125 ml of pyridine cooled in an ice bath, a solution containing 4.7 g of chloride is added with stirring over 10 minutes. 2,2-dimethylpropanoyl in 20 ml of ethylene chloride. The reaction mixture is stirred with cooling for another hour and then for 90 minutes without cooling. The reaction mixture is concentrated in vacuo to a volume less than 100 ml and then dropped into 300 ml of water containing an excess of 2N potassium hydroxide solution. The precipitated solid is recrystallized from 100 ml of isopropyl alcohol, dried under vacuum at 90 ° C. for more than 3 hours and then dissolved in 150 ml of methanol and

  treat the resulting solution with an excess of hydrochloric acid

  dries in ethanol. To the resulting mixture, chloroform is added, the solid which separates is collected and dried under vacuum at 90 ° C. for 16 hours, which gives

  8.67 g, as yellow-brown prisms, 2,2-dimethyl-

  N- [4- (4-pyridinyl) phenyl] propanamide in the form of its hydrochloride, mp 277-282 C. The product is obtained from the liquor

  additional 1.30 g of product, m.p. 274-279 C.

Example 8

  4-oxo-4- [4- (4-pyridinyl) phenylamindec butanoic acid A mixture is stirred at reflux for 10 hours.

  containing 50 g of 4- (4-pyridinyl) benzene-amine, 32 g of anhydrous

  succinic acid and 1 liter of chloroform and then filtered.

  On cooling, the filtrate gives a yellow crystalline product which is collected and dried under vacuum at 90 ° C.

  for 16 hours, to obtain 77.2 g of product, m.p. 251-

  251.5 ° C. 10 g of this product are recrystallized from 200 ml of acetic acid, the hot solution being filtered and

  allowing the filtrate to cool to room temperature.

  The solid which separates is collected and dried under vacuum at 90 ° C. on sodium hydroxide for 16 hours.

  and 4.57 g of 4-oxo-4- [4- (4-pyridinyl) -

  phenylamino] butanoic acid, m.p. 256-257 C.

Example 9

  N- [4- (4-pyridinyl) phenyl) phenyl] -2-butenamide is stirred at room temperature for 2 hours then

  at reflux for 16 hours a mixture containing 6.8 g of 4- (4-

  pyridinyl) benzene amine, 17.8 ml of crotonic anhydride and 1 ml of chloroform. The suspension is filtered and the filter cake is suspended in water plus ammonium hydroxide solution and refiltered to give 3.86 g of light brown solid after air drying. on the funnel. The chloroformic filtrate is concentrated in vacuo and the brown-yellow residue is suspended in a mixture of water and ammonium hydroxide, and the mixture is filtered to give more brown-yellow solid. The dimethylformamide is taken up in them. brown solids combined, the hot solution is filtered and the filtrate is concentrated to less than 300 ml and then treated with a

  slight excess of methanesulfonic acid in methanol.

  The resulting mixture is diluted with ether, the separating product is collected and dried under vacuum at 125 ° C. for 14 hours to give 4.31 g of N-R- (4-pyridinyl) methanesulphonate. phenyl] -2-butenamide, pof. 247-249 Co The following examples 10 and 11 show the preparation

  of two new N-acyl derivatives of 4- (4-pyridinyl) -

  benzene-amine, which can not be used as cardiotonic agents and therefore do not belong to the field

  claims of the present patent application; these

  examples are included here for comparison purposes as it is

  see below in the discussion of cardio-

  tonic of useful cardiotonic agents covered by the

appended claims.

Example 10

  3-Methyl-N- [4- (4-pyridinyl) phenyl] butanamide To 8.51 g of 4- (4-pyridinyl) benzene-amine in 125 ml of pyridine cooled in an ice-bath is added with stirring at room temperature. minutes a solution containing 7.72 g of 3-methylbutanoic acid chloride in 25 ml of ethylene chloride. The resulting mixture is stirred by cooling in the ice bath for about 90 minutes and then at room temperature for about 16 hours. The reaction mixture is then heated on a steam bath for 90 minutes and filtered hot on diatomaceous earth. The filtrate is diluted with water and then basified with ammonium hydroxide solution. When an oily material is separated only, the mixture is concentrated in vacuo and the resulting brown yellow solid is collected, washed with

  dilute solution of ammonium hydroxide and then with water.

  The solid is recrystallized from 150 ml of isopropyl alcohol and the solution is diluted with an aqueous solution of ammonium hydroxide. The solid which separates is collected and dried under vacuum at 90 ° C. for 20 hours to give 52 g of 3-methyl-N- [4- (4-pyridinyl) phenyl] butanamide, m.p. 166-176 C. This compound is dissolved in 250 ml of methanol and the solution is treated with an excess of hydrochloric acid in ethanol and then diluted with ether. The product which precipitated was collected and dried at 85 ° C. under vacuum for 60 hours to give 8.2 g of 3-methyl-N- [4- (4-pyridinyl) phenylbutanamide hydrochloride.

m.p. 257-264 C.

Example 11l

  N- 4- (4-Pyridinyl) phenyl] butanamide To a mixture containing 19.6 g of n-butanoic anhydride in 150 ml of chloroform, 6.81 g of 4- (4-pyridinyl) benzene are added with stirring. -amine, and the resulting mixture is stirred at room temperature for 17 hours and then refluxed for 90 minutes with stirring. The reaction mixture is filtered hot on diatomaceous earth and the filtrate is concentrated on a steam bath to drive off the solvent. The residue is diluted with water, the aqueous mixture is basified with ammonium hydroxide and the resulting mixture is stirred, concentrated again to remove a small amount of remaining chloroform, and the resulting solid is collected. . The solid is recrystallized from ethanol (150 ml) and water and dried in vacuo at 90 ° C. for 20 minutes.

  hours, to give 8.2 g of N- [4- (4-pyridinyl) phenyl] -

  butanamide, m.p. 174-175 C. This solid is then dissolved in 250 ml of methanol and the solution is treated with an excess of hydrochloric acid in ethanol, and the resulting mixture is diluted with ether. The separating product is collected, dried at 80-85 ° C. under vacuum for 60 hours.

  hours, and 8.79 g of N- [4- (4-

  pyridinyl) phenyl] butanamide, m.p. 289-293 C.

  The utility of the compounds of formulas I and II and their salts as cardiotonic agents is demonstrated by their efficacy in pharmacological test procedures.

  classics, for example in that they cause an increase in

  Significant reduction in the contraction force of isolated papillary and papillary muscles of cats and / or in causing a significant increase in cardiac contraction force in the anesthetized dog, with low or minimal changes in heart velocity

  and blood pressure. Descriptions

  detailed of these test procedures in the patent

United States of America N 4,072,746.

  When tested by the procedures on isolated papillary and papillary muscles of cats, it is found that the compounds of formulas I and II or their pharmaceutically acceptable acid addition salts cause at doses of 10, 30, 100 and / or or 300 fg / ml, significant increases, ie greater than 25%, in the strength of the papillary muscles and significant increases, ie greater than 25%, in the strength of the right atrium while causing a percentage increase

  lower (about half or less of the percentage increase

  the strength of the right atrium or the strength of the

  papillary muscle) of the speed of the right atrium.

  For example, when tested at the doses indicated by this procedure, the following compounds are found to cause increases of 50% or more in the strength of the papillary muscles and / or the strength of the right atrium: compounds of the examples 1, 2, 3, 4, 5, 6, 8 and 9. It is found that the preferred compounds of Examples 1, 2, 3, 4, 5 and 6 as well as that of Example 9, cause increases of 100% and more of the strength of the papillary muscles and / or the strength of the right atrium. The known compounds of formula I found to cause increases in papillary muscle strength of 80% or more at one or more of the indicated doses when tested by

  The above procedure is: 3- (4-pyridinyl) benzenamine, 4- (4-pyridinyl) benzene-amine, 3- (2-ethyl-4-

  pyridinyl) benzene-amine, 3- (2,5-dimethyl-4-pyridyl) benzene

  amine, 3- (2,6-dimethyl-4-pyridinyl) benzene-amine, 3- (2-

  hydroxy-6-methyl-4-pyridinyl) benzene-amine and N- [3- (4-

  pyridinyl) phénylJacétamide. When tested by the procedure on anesthetized dogs, it is found that the compounds of formulas I and II or their pharmaceutically acceptable acid addition salts, at doses of 1.0, 3.0 and / or 10 mg / kg administered intravenously, cause significant increases, that is, 25% or more, in cardiac contraction force or cardiac contractility, with lower changes in heart rate and blood pressure. For example, when tested at the doses indicated by this procedure, the following compounds are found to cause increases of 50% and more in the contraction force and lower changes in heart rate and blood pressure:

  compounds of Examples 1 to 9 inclusive. We find that

  Preferred embodiments of Examples 1 to 6 included increases in contraction strength of 90% and above at one or more dose levels in this test in the anesthetized dog. Known compounds causing a contraction force increase of 50% or greater in this test are 3- (4-pyridinyl) benzene amine and 4- (4-pyridinyl) benzene amine. Compounds found to be unsatisfactory as cardiotonic agents when tested by one or both of the above-mentioned tests on cat atria in vitro and on dogs anesthetized in vivo, include the compounds of Examples and 11 as well as N- [3- (4-pyridinyl) phényllpropionamide,

  N-1- [4- (4-pyridinyl) phenyl] acetamide and N- [3- (4-pyridinyl) -

  phenyl] formamide. When tested according to other conventional pharmacological test procedures, certain compounds of formulas I and II and their salts are found to have antihypertensive activity. For example, it is found that the compounds

  Examples 1-7 and 3- (2,6-dimethyl-4-pyridinyl) benzene;

  known amines have oral AHD40 values of 50, 40 and

  mg / kg respectively when tested in spontaneous rats.

  hypertensive similarly, it is found that the compounds of Examples 3 and 4 have lower antihypertensive activities (32% and 35% reduction in pressure at 50 and 150 mg / kg orally, respectively) when tested by this

operating mode.

  In clinical practice, a cardiotonic compound of formula I or II or a salt thereof will normally be administered orally or parenterally in a wide variety of dosage forms. Solid compositions for oral administration include tablets, pills, powders and granules. In such solid compositions, at least one of the active compounds ismixed with at least one inert diluent such as starch, calcium carbonate, sucrose or lactose. These compositions may also contain additional substances other than inert diluents, for example lubricating agents such as sodium stearate.

magnesium, talc, etc.

  Liquid compositions for administration by

  oral route include emulsions, solutions, suspen-

  sions, -sirops and elixirs, pharmaceutically acceptable

  tick, containing commonly used inert diluents

  in the field, like water and liquid paraffin. In-

  outside of the inert diluents, such compositions may also contain adjuvants, such as wetting agents

  and suspending agents, and sweetening, aromatic and

  health, fragrance and preservation. According to the invention,

  compositions for oral administration comprising

  capsules of absorbable materials such as gelatin, containing the active compound with or without

diluents or excipients.

  The preparations according to the invention intended for the administration

  Parenteral routes include sterile aqueous, aqueous-organic and organic solutions, suspensions and emulsions. Examples of organic solvents or suspending media are propylene glycol, polyethylene glycol, vegetable oils such as olive oil and injectable organic esters such as ethyl oleate. These compositions may also contain adjuvants such as stabilizers, preservatives, wetting agents, emulsifiers and the like.

dispersants.

  They can be sterilized, for example, by filtration on a filter retaining bacteria, by incorporation of sterilizing agents into the compositions, by irradiation or by heating. They can also be prepared as sterile solid compositions which can be dissolved in sterile water or any other sterile injectable medium,

immediately before use.

  Component percentages can be varied

  active in the composition intended to increase the contrac-

  cardiac function, so as to obtain an appropriate dose.

  The dose administered to a particular patient is variable, according to the judgment of the physician using as criteria: the route of administration, the duration of treatment, the size and condition of the patient, the potency of the active component and the patient's response to this compound. An effective dose of active component can therefore only be determined by the physician considering all the criteria and using his

  better judgment on the patient's behavior.

Claims (10)

  A cardiotonic composition for increasing cardiac contractility, said composition comprising a pharmaceutically acceptable inert carrier and being characterized by containing, as an active ingredient,   an effective amount of a [47 4- (or 3) - AcNH-phenyl] -   2-R2-3-R3-5-R5-6-R6-pyridine cardiotonic of formula I t2 / R3 NOT NHAc R6 R5   R 2 is a hydrogen atom or a methyl, ethyl or hydroxy group, R 6 is a hydrogen atom or a methyl or ethyl group, R 3 and R 5 are each a hydrogen atom or a methyl group and Ac is an atom of hydrogen or a hydroxyacetyl, acetoxyacetyl, d-hydroxypropionyl, a-acetoxypropionyl, methoxyacetyl, 2-butenoyl or carbamyl group and, when NHAc is attached to the 4-position of the phenyl ring, Ac may also be a group   formyl, n-propanoyl, 2,2-dimethyl-n-propanoyl or 3-   carboxypropanoyl and when NHAc is attached to the 3-position of the phenyl ring, Ac may also be an acetyl group, or a pharmaceutically acid addition salt thereof acceptable.   2. Composition according to claim 1, characterized in that R6 is a hydrogen atom or a methyl group, and Ac is a hydrogen atom, a formyl group (in the case defined in claim 1),   (-hydroxyacetyl, c-hydroxypropionyl or carbamoyl.   3. Composition according to claim 1, characterized   in that the cardiotonic compound is N- [4- (4-pyridinyl) -   phenyl] formamide or an acid addition salt thereof pharmaceutically acceptable.   4. Composition according to claim 1, characterized in   what the cardiotonic compound is 1-hydroxy-N- [4- (4-   pyridinyl) phenyl] propanamide, or an addition salt thereof   of pharmaceutically acceptable acid.   1 8 5. Compound used to increase cardiac contractility in a patient in need of such treatment, which is a cardiotonic compound of formula I according to one of   any of claims 1 to 4.   6. 4- [4 (or 3) -Ac'-NH-phenyl] -2-R2-3-R3-5-R5-6-R6-pyridine of formula II R2 R 3 Ni <> NHAc ' R6 R5   R2 is a hydrogen atom or a methyl group; ethyl or hydroxy, R6 is a hydrogen atom or an ethyl or methyl group, R3 and R5 are each a hydrogen atom   or a methyl group and Ac 'is a hydroxyl group   acetyl, acetoxyacetyl, oX-hydroxypropionyl, o-acetoxy-   propionyl, methoxyacetyl, 2-butenoyl or carbamyl, and when NHAc 'is attached to the 2-position of the phenyl ring,   also be a formyl, n-propanoyl group, 2,2-   dimethylpropanoyl or 3-carboxypropanoyl, or a salt thereof acid addition.   7. Compound according to claim 6, wherein R6 is a hydrogen atom or a methyl group and Ac 'is a hydroxyacetyl, hydroxypropionyl, carbamyl or formyl group.   or n-propanoyl (as defined above).   8. N- [4- (4-pyridinyl) phenyl] oramide or a salt thereof   of pharmaceutically acceptable acid addition.   9. 2-Hydroxy-N-4- (4-pyridinyl) phenylpropanamide or a pharmaceutically acid addition salt thereof acceptables.-   Process for the preparation of a compound according to Claim 6 or an acid addition salt thereof   characterized by reacting a 4-L4- (or 3) -   corresponding aminophenyl3-2-R2-3-R3-5-R5-6-R6-pyridine, with an acylating agent providing Ac ', and, if desired, converting the obtained free base into one of its salts acid addition.